Method of polishing implantable medical devices to lower thrombogenecity and increase mechanical stability

ABSTRACT

The present invention relates to a method of polishing an implantable medical device. The method may include positioning an implantable medical device on a support. At least a portion of a surface of the implantable medical device may include a polymer. A fluid may be contacted with at least a portion of the surface of the positioned implantable medical device. In an embodiment, the fluid may be capable of dissolving at least a portion of the polymer at or near the surface of the implantable medical device. The method may further include allowing the fluid to modify at least a portion of the surface of the positioned medical device. A majority of the contacted fluid may be removed from the surface of the implantable medical device. In certain embodiments, the modified portion of the surface may be substantially less thrombogenetic and substantially more mechanically stable than an unmodified surface.

CROSS-REFERENCE

This is a continuation of application Ser. No. 10/871,404 filed on Jun.18, 2004 which is a continuation-in-part of application Ser. No.10/603,889 filed on Jun. 25, 2003, which is now U.S. Pat. No. 7,285,304,both of which are incorporated by reference herein.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention is directed to methods for polishing implantable medicaldevices, such as stents, for lower thrombogenecity and improvedmechanical performance.

2. Description of the State of the Art

Percutaneous transluminal coronary angioplasty (PTCA) is a procedure fortreating heart disease. A catheter assembly having a balloon portion isintroduced percutaneously into the cardiovascular system of a patientvia the brachial or femoral artery. The catheter assembly is advancedthrough the coronary vasculature until the balloon portion is positionedacross the occlusive lesion. Once in position across the lesion, theballoon is inflated to a predetermined size to radially compress againstthe atherosclerotic plaque of the lesion to remodel the lumen wall. Theballoon is then deflated to a smaller profile to allow the catheter tobe withdrawn from the patient's vasculature.

A problem associated with the above procedure includes formation ofintimal flaps or torn arterial linings which can collapse and occludethe conduit after the balloon is deflated. Moreover, thrombosis andrestenosis of the artery may develop over several months after theprocedure, which may require another angioplasty procedure or a surgicalby-pass operation. To reduce the partial or total occlusion of theartery by the collapse of arterial lining and to reduce the chance ofthe development of thrombosis and restenosis, a stent is implanted inthe lumen to maintain the vascular patency.

Stents are used not only as a mechanical intervention but also as avehicle for providing biological therapy. As a mechanical intervention,stents act as scaffoldings, functioning to physically hold open and, ifdesired, to expand the wall of a passageway. Typically, stents arecapable of being compressed or crimped, so that they can be inserted ordelivered through small vessels via catheters, and then expanded ordeployed to a larger diameter once they are at the desired location. Inaddition, biological therapy can be achieved by medicating the stents.Medicated stents provide for the local administration of a therapeuticsubstance at the diseased site. One proposed method for medicatingstents involves the use of a polymeric carrier coated onto the surfaceof a stent. A blend which includes a solvent, a polymer dissolved in thesolvent, and a therapeutic substance dispersed in the blend is appliedto the stent. The solvent is allowed to evaporate, leaving on the stentsurface a coating of the polymer and the therapeutic substanceimpregnated in the polymer.

Stents have been made of many materials including metals and polymericmaterials such as plastic, including biodegradable plastic materials.Stents have been formed from wire, tube stock, etc. Stents have alsobeen made from sheets of material which are rolled into a cylindricalshape. A medicated stent may be fabricated by coating the surface ofeither a metal or polymeric scaffolding or substrate with a polymericcarrier. A drug can also be incorporated into a polymer from which astent is made. In addition, the structure of a stent is typicallycomposed of a pattern that allows the stent to be radially expandable.The pattern should be designed to maintain the necessary longitudinalflexibility and radial rigidity of the stent. Longitudinal flexibilityfacilitates delivery of the stent and radial rigidity is needed to holdopen a bodily lumen.

The biocompatibility of an implantable medical device, such as a stent,is extremely important for successful treatment of a bodily lumen. Onemeasure of biocompatibility is the tendency for an implantable medicaldevice to form thrombus. The surface finish of an implantable medicaldevice is an important factor in thrombus formation. Certain surfacefeatures such as cracks, pits, or jagged edges substantially increaseformation of thrombus. Such imperfections tend to be a by-product of afabrication process. In addition, imperfections in the surface of animplantable medical device may cause mechanical instability. Surfacecracks or other imperfections tend to serve as sites at which stressapplied to an implantable medical device is concentrated. Therefore,imperfections can result in the enlargement of existing cracks orformation of new cracks. This can occur when stress is applied to theimplantable medical device, for example, during crimping or deployment.

SUMMARY

The present invention is directed to embodiments of a method ofpolishing an implantable medical device. In one embodiment, the methodmay include positioning an implantable medical device on a support. Atleast a portion of a surface of the implantable medical device mayinclude a polymer. The method may further include contacting a fluidwith at least a portion of the surface of the positioned implantablemedical device. The fluid may be capable of dissolving at least aportion of the polymer at or near the surface of the implantable medicaldevice. In some embodiments, the fluid may be allowed to modify at leasta portion of the surface of the positioned medical device. In certainembodiments, the method may further include removing all or a majorityof the contacted fluid from the surface of the implantable medicaldevice. The modified portion of the surface, after removal of thecontacted fluid, may be less thrombogenetic and more mechanically stablethan an unmodified surface.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts a stent.

FIGS. 2 and 3 depict diagrams of a surface of a stent.

FIG. 4 depicts a stent positioned on a mandrel.

FIGS. 5 and 6 depict optical micrographs of stents.

FIGS. 7 and 8 depict SEM images of the surface of a stent.

FIGS. 9 and 10 depict measured thrombosis on stents.

DETAILED DESCRIPTION OF THE INVENTION

For the purposes of the present invention, the following terms anddefinitions apply:

“Thrombosis” refers to the formation or presence of a blood clot or“thrombus” within a blood vessel. The blood clot results fromaggregation of blood components, primarily fibrin and platelets. Thethrombus frequently results in vascular obstruction.

“Lysis” refers to a process of disintegration or dissolution, forexample, of cells.

“Pseudopodia” refers to a temporary protrusion or retractile process ofthe cytoplasm of a cell that functions in a locomotive or food gatheringcapacity.

When referring to a polymeric surface of an implantable medical device,unless otherwise specified, this includes a device made from a polymeror coated with a polymer. The underlying substrate that is coated can bepolymeric, metallic, ceramic, or made from any suitable material. Thepolymer surface of an implantable medical device often includes varioustypes of imperfections or features that tend to make the device moresusceptible to thrombosis and/or mechanical instability. Suchimperfections or features tend to activate fibrin and/or platelets toform thrombus. These imperfections are often formed during thefabrication of the implantable medical device. For example, theimperfections may be a by-product of an injection molding process or acoating process. The imperfections may include cracks, pitting, and/orjagged edges. FIG. 1 depicts a stent 10 that includes struts 12 with asurface 16. FIG. 2 depicts a surface 20 which is an expandedcross-section of a portion of surface 16 of stent 10. Surface 20includes a jagged edge 24, a crack 26, and a pit 28.

The presence of such imperfections on the surface of an implantablemedical device tends to facilitate the rapid formation of thrombus whenimplanted in a bodily lumen. It is believed that thrombus formation isfacilitated by such imperfections. Without being bound by any particulartheory, imperfections on a surface may serve as sites at which plateletsmay attach which may then lead to thrombus formation. Removing and/orreducing such imperfections may decrease the number of sites forattachment to a surface and/or reduce the tendency for platelets toattach to a surface, respectively, of an implantable medical device.Therefore, thrombus formation may be significantly reduced. Reducing animperfection may refer to reducing the degree or size of an imperfectionin a way that improves surface quality. For example, reducing animperfection may correspond to smoothing a jagged edge. FIG. 3 depicts asurface 30 which is another expanded cross-section of surface 16 ofstent 10 depicted in FIG. 1. Feature 32 may result in significantly lessplatelet attachment than jagged edge 24 in FIG. 2. As a result, surface30 may result in significantly less thrombosis than surface 20 proximateto jagged edge 24. Therefore, it may be advantageous to modify thesurface of an implantable medical device to reduce or removeimperfections from the surface to reduce thrombus formation.

Furthermore, the presence of features such as cracks or pitting in animplantable medical device may cause mechanical instability in theimplantable medical device. In general, some features, in particularcracks, tend to result in stress concentration localized at or near theimperfection. Such features may be referred to as “stressconcentrators.” Irregularities or discontinuities in the shape of anobject, such as crack 26 in FIG. 2, result in steep gradients of stressat or near the irregularity or discontinuity. Stress is concentrated atan irregularity or discontinuity because a load on an object cannot beuniformly distributed across the full area of the object. Therefore, theload must be redistributed across a missing cross-section of the object.Moreover, stress concentrators may lead to failure of a material sincefracture always starts at some point of stress concentration. Failureand fracture mechanics of polymers and other types of materials are wellknown and are discussed in many publications, for example, “Deformationand Fracture Mechanics of Engineering Materials,” Richard W. Hertzberg,4th edition, John Wiley & Sons, December 1995.

Implantable medical devices are subjected to stress both before andduring treatment. For example, implantable medical devices are placedunder stress during crimping and deployment. Therefore, it may bedesirable to modify the surface of an implantable medical device toreduce or remove imperfections from its surface to increase mechanicalstability of the implantable medical device.

The method described herein may be particularly useful for implantablemedical devices in which at least a portion of the surface of theimplantable medical device is polymeric. The device can be madepartially or completely from a biodegradable, bioabsorbable, orbiostable polymer. The polymer may be purified. A polymer-fabricateddevice may serve as a substrate for a polymer-based coating. Thepolymer-based coating may contain, for example, an active agent or drugfor local administration at a diseased site. Alternatively, animplantable medical device may include a non-polymer substrate with apolymer-based coating. Examples of implantable medical devices includeself-expandable stents, balloon-expandable stents, stent-grafts, grafts(e.g., aortic grafts), artificial heart valves, cerebrospinal fluidshunts, pacemaker electrodes, and endocardial leads (e.g., FINELINE andENDOTAK, available from Guidant Corporation, Santa Clara, Calif.). Theunderlying structure or substrate of the device can be of virtually anydesign. A non-polymer substrate of the device may be made of a metallicmaterial or an alloy such as, but not limited to, cobalt chromium alloy(ELGILOY), stainless steel (316 L), high nitrogen stainless steel, e.g.,BIODUR 108, cobalt chrome alloy L-605, “MP35N,” “MP20N,” ELASTINITE(Nitinol), tantalum, nickel-titanium alloy, platinum-iridium alloy,gold, magnesium, or combinations thereof. “MP35N” and “MP20N” are tradenames for alloys of cobalt, nickel, chromium and molybdenum availablefrom Standard Press Steel Co., Jenkintown, Pa. “MP35N” consists of 35%cobalt, 35% nickel, 20% chromium, and 10% molybdenum. “MP20N” consistsof 50% cobalt, 20% nickel, 20% chromium, and 10% molybdenum.

Polymers can be biostable, bioabsorbable, biodegradable or bioerodable.Biostable refers to polymers that are not biodegradable. The termsbiodegradable, bioabsorbable, and bioerodable are used interchangeablyand refer to polymers that are capable of being completely degradedand/or eroded when exposed to bodily fluids such as blood and can begradually resorbed, absorbed, and/or eliminated by the body. Theprocesses of breaking down and eventual absorption and elimination ofthe polymer can be caused by, for example, hydrolysis, metabolicprocesses, bulk or surface erosion, and the like. For coatingapplications, it is understood that after the process of degradation,erosion, absorption, and/or resorption has been completed, no polymerwill remain on the device. In some embodiments, very negligible tracesor residue may be left behind. For stents made from a biodegradablepolymer, the stent is intended to remain in the body for a duration oftime until its intended function of, for example, maintaining vascularpatency and/or drug delivery is accomplished.

An implantable medical device, such as a stent can be completely or atleast in part be made from a biodegradable polymer or combination ofbiodegradable polymers, a biostable polymer or combination of biostablepolymers, or a combination of biodegradable and biostable polymers. Insome embodiments, a surface of an implantable medical device such as astent can be coated with a biodegradable polymer or combination ofbiodegradable polymers, a biostable polymer or combination of biostablepolymers, or a combination of biodegradable and biostable polymers.

Representative examples of polymers that may be used in fabricating animplantable medical device using the methods disclosed herein includepoly(N-acetylglucosamine) (Chitin), Chitoson, poly(hydroxyvalerate),poly(lactide-co-glycolide), poly(hydroxybutyrate),poly(hydroxybutyrate-co-valerate), polyorthoester, polyanhydride,poly(glycolic acid), poly(D,L-lactic acid), poly(glycolicacid-co-trimethylene carbonate), poly(trimethylene carbonate),co-poly(ether-esters) (e.g. PEO/PLA), polyphosphazenes, biomolecules(such as fibrin, fibrinogen, cellulose, starch, collagen and hyaluronicacid), polyurethanes, silicones, polyesters, polyolefins,polyisobutylene and ethylene-alphaolefin copolymers, acrylic polymersand copolymers other than polyacrylates, vinyl halide polymers andcopolymers (such as polyvinyl chloride), polyvinyl ethers (such aspolyvinyl methyl ether), polyvinylidene halides (such as polyvinylidenechloride), polyacrylonitrile, polyvinyl ketones, polyvinyl aromatics(such as polystyrene), polyvinyl esters (such as polyvinyl acetate),acrylonitrile-styrene copolymers, ABS resins, polyamides (such aspolyester amides, Nylon 66, and polycaprolactam), polycarbonates,polyoxymethylenes, polyimides, polyethers, polyurethanes, rayon,rayon-triacetate, cellulose acetate, cellulose butyrate, celluloseacetate butyrate, cellophane, cellulose nitrate, cellulose propionate,cellulose ethers, and carboxymethyl cellulose. Additional representativeexamples of polymers that may be especially well suited for use inmanufacturing an implantable medical device according to the methodsdisclosed herein include ethylene vinyl alcohol copolymer (commonlyknown by the generic name EVOH or by the trade name EVAL), poly(butylmethacrylate), poly(vinylidene fluoride-co-hexafluororpropene) (e.g.,SOLEF 21508, available from Solvay Solexis PVDF, Thorofare, N.J.),polyvinylidene fluoride (otherwise known as KYNAR, available fromATOFINA Chemicals, Philadelphia, Pa.), poly(L-lactic acid),poly(caprolactone), ethylene-vinyl acetate copolymers, and polyethyleneglycol.

Some embodiments of a method of polishing a stent surface may use afluid that is a solvent for the polymeric surface of the stent.“Solvent” is defined as a substance capable of dissolving or dispersingone or more other substances or capable of at least partially dissolvingor dispersing the substance(s) to form a uniformly dispersed mixture atthe molecular- or ionic-size level. The solvent should be capable ofdissolving at least 0.1 mg of the polymer in 1 ml of the solvent, andmore narrowly 0.5 mg in 1 ml at ambient temperature and ambientpressure. A second fluid can act as a non-solvent for the impurity.“Non-solvent” is defined as a substance incapable of dissolving theother substance. The non-solvent should be capable of dissolving onlyless than 0.1 mg of the polymer in 1 ml of the non-solvent at ambienttemperature and ambient pressure, and more narrowly only less than 0.05mg in 1 ml at ambient temperature and ambient pressure.

An embodiment of a method of polishing an implantable medical device mayinclude positioning an implantable medical device on a support. At leasta portion of the surface of the implantable medical device may becomposed of a polymer. The method may further include contacting a fluidwith at least a portion of the surface of the positioned implantablemedical device. The fluid may be capable of dissolving at least aportion of the polymer at or near the surface of the implantable medicaldevice. In certain embodiments, the fluid may be allowed to modify atleast a portion of the surface of the positioned implantable medicaldevice. In one embodiment, the fluid is free (100%) from any polymericmaterials, active agents, or drugs. The fluid can be a pure solvent or acombination of one or more pure solvents. The method may then includeremoving all or a majority of the contacted fluid from the surface ofthe implantable medical device. After removal of the contacted fluid,the modified portion of the surface may be less thrombogenetic and moremechanically stable than an unmodified surface.

Additionally, some embodiments of the method may further includeremoving at least some impurities at or near the surface of theimplantable medical device prior to contacting the surface of theimplantable medical device with the fluid. Impurities may includeparticles and/or contaminants that may reduce the effectiveness of thepolishing process. One method of removing impurities may includeultrasonic cleaning. In an ultrasonic cleaning process the implantablemedical device may be immersed in a bath of a suitable fluid.Representative examples of suitable fluids may include alcohols such asisopropyl alcohol, water, or any other fluid that is inert to thepolymer during the time frame of the cleaning process. Removal ofimpurities may be achieved by subjecting the bath to ultrasoniccavitation. Cavitation refers to the formation of partial vacuums in aliquid. Standard ultrasonic baths operate at a frequency of about 40kHz. The implantable medical device may be subjected to the ultrasonicbath for about one minute to about ten minutes, or more narrowly fromabout one to about three minutes. Ultrasonic cleaning may be followed byrinsing and drying of the implantable medical device. Rinsing may beperformed with the cleaning solution. The device may be air dried, orbaked in an oven.

It is desirable to maximize the surface area of the implantable medicalthat is polished. Therefore the support for the implantable medicaldevice may be selected such that contact between the support and thedevice is minimized. In one embodiment, the implantable medical devicemay be positioned on a mandrel. A mandrel refers to a substantiallycylindrical shaft that may serve as an axis. Typically, a madrel isconfigured to rotate about its cylindrical axis. A substantiallycylindrical implantable medical device such as that depicted in FIG. 1may be positioned about the axis of the mandrel. A tubular mandrel thatis inserted into the bore of a stent can, however, mask the innersurface of the stent so as to prevent proper polishing of the innersurface of the stent. Accordingly, it is preferable to use a supportassembly that allows for proper access to the inner or luminal surfaceof the stent and not just the outer or abluminal surface of the stent.The mandrel can include, for example, a first element that supports afirst end of the stent and a second element that supports a second endof the stent. Examples in the patent literature teaching these types ofmandrels include U.S. Pat. No. 6,527,863 to Pacetti et al. and U.S. Pat.No. 6,605,154 to Villareal. The madrel, accordingly does not makecontact with a luminal surface of the stent and allows for propermodification of all surfaces.

Furthermore, contacting a fluid with at least a portion of a surface ofthe positioned implantable medical device may be performed in severalways. In one embodiment, contacting a fluid with at least a portion ofthe surface may include translating the positioned implantable medicaldevice through a stream of the fluid. In one embodiment, the stream maybe an atomized stream of small droplets. In addition, in someembodiments, the implantable medical device may be rotated during thecontacting of the fluid. For example, the medical device may bepositioned on a rotating mandrel. Rotation may facilitate a more uniformand complete coverage of the fluid on the surface of the implantablemedical device. FIG. 4 depicts implantable medical device 10 from FIG. 1positioned on mandrel 40. The mandrel may be rotated about axis 42during the contacting of the fluid with the surface of the implantablemedical device.

In some embodiments, the stream of fluid can also be applied by sprayingthe fluid onto the stent with a conventional spray apparatus, or appliedby other metering devices. For instance, the stent can be sprayed forone to ten spray cycles (i.e., back and forth passes along the length ofthe stent) using a spray apparatus to deposit about 1 ml to about 500ml, more narrowly 5 ml to about 20 ml, of the fluid onto the stent. Thespray process can take place in a vacuum chamber at a reduced pressure(e.g., less than 300 mm Hg) in order to raise the fluid concentration inthe vapor phase.

Alternatively, a fluid may be contacted with the surface of theimplantable medical device by hand caulking with an applicator. Theapplicator may include a handle with material at one end soaked with thefluid. For example, the material may be a brush, sponge, or cloth. Inaddition, a fluid may be vapor deposited on the surface of theimplantable medical device. Additionally, an implantable medical devicemay be contacted with fluid by immersing the device in a bath of thefluid.

In certain embodiments, allowing the fluid to modify at least a portionof the surface of the implantable medical device may include allowingthe fluid to reduce and/or remove all or a substantial portion ofundesirable features from the surface that facilitate thrombosis on ormechanical instability of the implantable medical device. Since thefluid is capable of dissolving the polymer, the fluid may dissolve atleast a portion of the surface of the implantable medical device to forma polymer solution. Representative examples of fluids that may be usedto polish an implantable medical device include chloroform, acetone,chlorobenzene, ethyl acetate, 1,4-dioxane, ethylene dichloride,2-ethyhexanol, and combinations thereof. The polymer solution may tendto flow at or near the surface. The formation and flow of the polymersolution may act to substantially reduce and/or remove features thatfacilitate thrombosis on or mechanical instability of the implantablemedical device. In an embodiment, the fluid may be allowed to modify thesurface of the positioned implantable medical device for a selectedperiod of time prior to removal from the surface.

In some embodiments, the fluid may be selected to achieve a desireddegree of modification during a selected period of time. Equivalently,the fluid may be selected to dissolve polymer to a desired degree duringa selected period of time. Generally, the greater the solubility of thepolymer in a fluid, the greater the amount of polymer dissolved at ornear the surface of the implantable medical device. A parameter that isuseful in characterizing the tendency of a fluid to dissolve a polymeris the solubility parameter, δ. A widely accepted unit of the solubilityparameter is the Hildebrand, which is equal to 1 (cal/cm³)^(1/2).Solubility parameters of selected fluids are shown in Table 1. TABLE 1Solubility parameters of fluids at 25° C. Fluid Solubility Parameter(cal/cm³)^(1/2) Chloroform 9.3 Acetone 10.0 Chlorobenzene 9.5 Ethylacetate 9.1 Ethylene dichloride 9.8 2-ethyhexanol 9.5 1,4-dioxane 9.9

It is expected that the greatest tendency of a polymer to dissolveoccurs when its solubility parameter substantially matches that of thesolvent. A fluid with a tendency to dissolve a polymer that is too highmay cause an undesirable degree of modification of the surface beforethe fluid can be removed. Alternatively, a fluid with a tendency todissolve polymer that is too low, may require too long of a time toachieve a desired degree of modification, reducing manufacturingefficiency. In addition, a fluid may be selected based on otherparameters such as viscosity and the ability of the fluid to flow acrossthe surface of the surface of the polymer.

In some embodiments, the tendency of a fluid to dissolve a polymer maybe optimized. For instance, the fluid may be a mixture of two or morefluids. The polymer may be insoluble or substantially insoluble in atleast one of the fluids. For instance, at least one of fluids may be anon-solvent for the polymer. For example, chloroform has a tendency todissolve poly(D,L-lactic acid), while poly(D,L-lactic acid) issubstantially insoluble in methanol. Since chloroform and methanol aremutually soluble, a fluid with a desired tendency to dissolve thepolymer may be attained by adjusting the ratio of the components in amixture.

Additionally, if a polymer stent surface contains a drug, it may bedesirable to select a solvent that is a non-solvent for the drug. Theuse of a fluid that is a mutual solvent for both the polymer and thedrug may be undesirable because the solvent may act as a stimulus to thedrug in the polymer. A stimulus increases the permeability of the drugin the polymer surface. As a result, a nonuniform composition of thedrug may be created with a concentration of drug greater near thepolished surface. In addition, the total drug content may be decreasedthrough dissolution of the drug in the solvent. A nonuniform compositionof the drug and a decrease in the drug content may both adversely affectthe treatment of a diseased site in a bodily lumen.

In an embodiment, a majority of the contacted fluid may be removed fromthe surface of the implantable medical device a selected period of timeafter contacting the fluid with at least a portion of the surface. Asdiscussed above, failure to remove the fluid may result in anundesirable degree of modification of the surface of the implantablemedical device. Some embodiments may include removing a majority of thecontacted fluid from the surface of the implantable medical device bycontacting or blowing the implantable medical device with a stream of aninert gas such as nitrogen, argon, etc. The inert gas may be contactedor blown on the device for between about 30 seconds to about threeminutes. The stent, mounted on a support, may be positioned betweenabout 1 mm and about 200 mm, or more narrowly between about 10 mm andabout 50 mm from a nozzle of an ejecting stream of inert gas. Thesupport may be rotated to facilitate uniform removal of the fluid fromthe stent. The flow rate of the gas may be optimized to obtain quick andefficient removal of the fluid without disturbing the surface structureof the stent. The inert gas may be at ambient temperature.Alternatively, the temperature of the inert gas stream may be at atemperature greater than ambient temperature and less than or equal tothe melting temperature of the polymer. The “melting temperature”,T_(m), of a polymer is the highest temperature at which a crystallattice in the polymer is stable. If the polymer includes an activeagent, it is desirable for the temperature of the polymer to be below arange at which the active agent may be degraded. A temperature range inwhich active agents may degrade may be at temperatures above about 100°C., or more narrowly, above about 80° C.

In some embodiments, the implantable medical device may be subjected toadditional processing to remove a substantial portion of any remainingfluid. In an embodiment, at least some fluid may be removed by applyingheat to the implantable medical device. For example, the implantablemedical device may be heated between about fifteen minutes and about 120minutes in an oven. The heating may be performed in a vacuum. Theapplication of heat can be performed after blowing of the inert gas.Heat may be applied within a range of temperature greater than ambienttemperature and less than the melting temperature of the polymer. Asmentioned above, if the polymer includes an active agent, it isdesirable for the temperature to be below a range at which the activeagent may be degraded.

EXAMPLE

Some embodiments of the present invention are illustrated by thefollowing Example. The Example is being given by way of illustrationonly and not by way of limitation. The Example illustrates the influenceof the method of polishing an implantable medical device on bloodbiocompatibility. The blood compatibility of five stents was measuredfrom two experimental runs. The parameters and data are not to beconstrued to unduly limit the scope of the embodiments of the invention.

Blood biocompatibility measurements were performed on a number of stentsusing the Chandler loop method. The Chandler loop method is well knownin the art and is described in detail elsewhere. Quart. J. Exp.Physiol., 46, 1 (1961), A. B. Chandler, Lab. Investigations, 1, 110(1958). The Chandler loop apparatus includes loops or tubes in whichtesting of an implantable medical device is performed. An implantablemedical device may be inserted into a loop along with blood. The loopsare then rotated for the duration of a test run to simulate flow in avessel.

Blood compatibility was evaluated and/or measured in three ways. First,some of the samples were inspected visually by an optical microscope.Second, the platelet morphology and fibrin structure of the stentsamples were examined using a scanning electron microscope (SEM).Finally, a quantitative measure of the thrombus formation was obtainedfrom measurement of fluorescently labeled platelets using a fluorescentplate reader.

The influence of polishing by methods disclosed herein onthrombogenecity was evaluated for a poly(lactic acid) (PLA) polymericstent with no coating and a PLA polymeric stent with a PLA coating. Eachof these stents was obtained from Bioabsorbable Vascular Solutions inMountainview, Calif. The unpolished and polished samples were preparedin two separate Chandler loop runs. Each Chandler loop run included acontrol stent. The control stent was used as a reference or control forevaluating the blood biocompatibility of the other stents in each run.The control stent in each run was a Solef-coated metallic Vision stentobtained from Guidant Corporation in Santa Clara, Calif. TheSolef-coated stent is a non-bioerodable bare metal stent (BMS) that isknown to have low thrombogenecity. A poly(n-butyl methacrylate) (PBMA)primer was used on the control stent. The primer is used to improveadhesion of the SOLEF to a substrate and also results in an acceptablylow thrombogenecity for the surface. All of the stents were 3 mm indiameter and 8 mm in length. A summary of the stents is shown in Table2. TABLE 2 Summary of the stents used in Chandler Loop tests. Stent #Stent Run Polished Stent Material Coating Primer 1 In-house 1 No PLA80/20 None None 2 In house 1 No PLA 80/20 Blend PLA 80/20 Blend, None115 μg 3 Vision 1 No Cobalt Chrome Solef, 311 μg PBMA (Control) 44 μg 4In-house 2 Yes PLA 80/20 Blend None None 5 In-house 2 Yes PLA 80/20Blend PLA 80/20 Blend, None 115 μg 6 Vision 2 No Cobalt Chrome Solef,311 μg PBMA (Control) 44 μg

The Chandler apparatus as used for this investigation can accommodate atotal of 24 loops. An “arm” of the apparatus corresponds to four loops.Each loop holds one stent and has an inside diameter of 3 mm. Foursamples of each stent were tested in each of the two runs. One of thefour samples was used for imaging and three of the samples were used foraverage thrombus quantification.

Fresh porcine blood was collected on the morning of the day of theexperimental runs. An anticoagulant, heparin, was added to the blood togive a concentration of 2 U/ml (units per ml) in the blood. In addition,a fluorescent dye, mepacrine HCl, was added to the whole blood as afluorescent tag for the platelets. Previous studies have reported aconcentration of 10 μMoles mepacrine did not alter platelet activity.

In each run, the stents were deployed individually in medical grade PVCtubing. 2.5 ml of the porcine blood was then added to each tube. Asleeve was used to close the loop on the outside diameter of each tube.Aside from the tubing lumen and the stent, no other foreign material wasexposed to the blood. The loops were then positioned on the Chandlerdevice and were allowed to run for 2 hours at 37° C. and 24 RPM which isequivalent to a 100 ml/min flow of blood in a 3.0 mm tube. After eachrun was completed, the blood was removed from each loop. Each of thestents was gently rinsed with phosphate buffered saline (PBS). One ofthe four stents in each arm was used for imaging and three of the fourwere used for thrombus quantification.

The stents for use in SEM imaging were fixed with 2.5% glutaraldehydefor an hour. The stents then underwent a serial exchange with increasingethanol in the next three hours to preserve the three-dimensionalstructure of the blood cells. The stents were then air dried overnight.Before imaging, the stents were inspected visually by opticalmicroscope. Finally, the stents were examined by a scanning electronmicroscope (SEM). Platelet morphology and fibrin structure were examinedby SEM at high magnifications. The morphology of the platelets isimportant for providing insight on whether or not the platelets werebeing activated by the coatings. In the worst case, activated plateletschange their shapes from a disc-like form to a globular form withpseudopodia extensions. The presence of fibrin mesh also indicates asevere thrombogenecity property of materials.

FIGS. 5 and 6 depict optical micrographs of stents #1 and #3. Anexamination of FIGS. 5 and 6 indicated that stent #1 resulted in morethrombus formation than the control stent, stent #3, in run 1.

FIGS. 7 and 8 depict SEM images of representative stents before andafter polishing, respectively. FIG. 7 depicts the surface of anunpolished stent and FIG. 8 depicts the surface of a polished stent.Polishing the stent has significantly reduced and/or eliminatedimperfections on the surface of the stent.

Thrombus formation may be quantified by measuring the fluorescentsignals from the mepacrine on blood cells that adhered to the stentsurface. Blood cells that adhered to the stent surface were lysed by 1%sodium dodecyl sulphate (SDS) to release mepacrine from the platelets.The fluorescent signals from the mepacrine in the supernatant werecollected and quantified by a fluorescent plate reader with anexcitation wavelength at 420 nm and an excitation wavelength at 500 nm.The amount of thrombus for each stent type was normalized to the controlstents in each run.

FIG. 9 shows the amount of platelets measured based on this methoddescribed above for run 1, the unpolished stents and the control. Thepercent error propagation is also shown. The y-axis is the percentthrombus collected on the stents normalized with respect to the controlstent #3. The values for each stent are an average of the measuredthrombus of three samples. FIG. 9 shows that the unpolished polymericstent #1 has more than 11 times the thrombus of the control stent #3.FIG. 9 shows that the unpolished, coated polymeric stent #2 has about2.4 times the thrombus of the control stent #3. FIG. 10 shows the amountof platelets measured based on this method described above for run 2,the polished stents, and the control stent. The polished, uncoatedpolymeric stent #4 has about 1.65 times the thrombus of the controlstent #6. The polished, coated stent #5 has slightly less thrombus thanthe control stent #6. The results of the two runs are summarized inTable 3. TABLE 3 Results of thrombus quantification. % of Control -Stent # Stent Run Polished Solef-coated BMS 1 In-house 1 No 1107.86 2In-house 1 No 242.59 3 Vision 1 No 100 (Control) 4 In-house 2 Yes 165.375 In-house 2 Yes 98.38 6 Vision 2 No 100 (Control)

These results demonstrate that polishing stents using the methodsdescribed herein can dramatically decrease thrombus formation on thesurface of the stents. However, the results of these tests may not beextrapolated significantly beyond the two hour time frame of thesetests. It is believed that a bioerodable polymer surface, such as a PLAsurface, and its degradation products may impact blood compatibility inlonger term tests.

1. A method of polishing an implantable medical device, comprising:contacting a fluid with at least a portion of a surface of animplantable medical device, wherein at least a portion of the surface ofthe implantable medical device comprises a polymer, the fluid beingcapable of dissolving the polymer; allowing the fluid to modify at leasta portion of the surface of the implantable medical device; and removingall or a majority of the contacted fluid from the surface of theimplantable medical device, wherein the modified portion of the surfaceafter removal of the contacted fluid is less thrombogenetic and moremechanically stable than an unmodified surface.
 2. The method of claim1, wherein the implantable medical device is a stent.
 3. The method ofclaim 1, wherein the polymer comprises a bioabsorbable polymer.
 4. Themethod of claim 1, wherein the polymer is selected from the groupconsisting of poly(N-acetylglucosamine), Chitoson, poly(trimethylenecarbonate) and copolymers thereof, an ethylene vinyl alcohol copolymer,poly(butyl methacrylate), poly(vinylidenefluoride-co-hexafluororpropene), polyvinylidene fluoride, poly(L-lacticacid), poly(D,L-lactic acid), poly(caprolactone), an ethylene-vinylacetate copolymer and polyethylene glycol.
 5. The method of claim 1,wherein the fluid is allowed to modify the surface of the positionedimplantable medical device for a selected period of time sufficient toreduce thrombogeneity and increase mechanical stability of the device.6. The method of claim 1, further comprising removing at least someimpurities at or near the surface of the implantable medical deviceprior to contacting the surface of the implantable medical device withthe fluid.
 7. The method of claim 1, wherein the fluid is selected fromthe group consisting of chloroform, acetone, chlorobenzene, ethylacetate, 1,4-dioxane, ethylene dichloride, 2-ethyhexanol, andcombinations thereof.
 8. The method of claim 1, wherein the fluidcomprises a mixture comprising at least two components, wherein thepolymer is insoluble in at least one of the components.
 9. The method ofclaim 1, wherein allowing the fluid to modify at least a portion of thesurface of the implantable medical device comprises allowing the fluidto reduce and/or remove all or a substantial portion of features fromthe surface of the implantable medical device that facilitate thrombosison or mechanical instability of the implantable medical device.
 10. Themethod of claim 9, wherein the features comprise imperfections at ornear the surface of the implantable medical device.
 11. The method ofclaim 9, wherein the features comprise at least one jagged portion at ornear the surface of the implantable medical device.
 12. The method ofclaim 9, wherein the features comprise at least one pit at or near thesurface of the implantable medical device.
 13. The method of claim 9,wherein the features comprise at least one crack at or near the surfaceof the implantable medical device.
 14. The method of claim 1, whereinallowing the fluid to modify at least a portion of the surface of theimplantable medical device comprises allowing the fluid to dissolve atleast a portion of the surface of the implantable medical device to forma polymer solution.
 15. The method of claim 14, wherein allowing thefluid to modify at least a portion of the surface of the implantablemedical device further comprises allowing the polymer solution to flowat or near the surface of the implantable medical device, and whereinthe formation and flow of the polymer solution act to substantially orcompletely reduce and/or remove features that facilitate thrombosis onor mechanical instability of the implantable medical device.
 16. Themethod of claim 1, wherein removing a majority of the contacted fluidfrom the surface of the implantable medical device comprises blowing aninert gas on the implantable medical device.
 17. The method of claim 16,wherein removing a majority of the contacted fluid from the surface ofthe implantable medical device further comprises exposing theimplantable medical device to heat and/or a vacuum.
 18. The method ofclaim 1, wherein the polymer surface contains a drug and the fluid is anon-solvent for the drug.